Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists

Frank W. Foss, Ashley H. Snyder, Michael D. Davis, Michael Rouse, Mark D. Okusa, Kevin R. Lynch, Timothy L. Macdonald*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P1-5). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P1 and S1P3 receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.

Original languageEnglish
Pages (from-to)663-677
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number2
DOIs
StatePublished - 15 Jan 2007
Externally publishedYes

Keywords

  • FTY720
  • Immune-modulation
  • Sphingosine 1-phosphate
  • VPC23019
  • VPC44116

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